Heterocyclic thioester and ketone hair growth compositions and uses

ABSTRACT

This invention relates to pharmaceutical compositions and methods for treating alopecia and promoting hair growth using heterocyclic thioesters and ketones.

This application is a continuation-in-part of U.S. patent applicationSer. No. 08/869,426, filed on Jun. 4, 1997, the entire contents of whichare herein incorporated by reference.

BACKGROUND OF THE INVENTION

1. Field of Invention

This invention relates to pharmaceutical compositions and methods fortreating alopecia and promoting hair growth using low molecular weight,small molecule heterocyclic thioesters and ketones.

2. Description of Related Art

Hair loss occurs in a variety of situations. These situations includemale pattern alopecia, alopecia senilis, alopecia areata, diseasesaccompanied by basic skin lesions or tumors, and systematic disorderssuch as nutritional disorders and internal secretion disorders. Themechanisms causing hair loss are very complicated, but in some instancescan be attributed to aging, genetic disposition, the activation of malehormones, the loss of blood supply to hair follicles, and scalpabnormalities.

The immunosuppressant drugs FK506, rapamycin and cyclosporin are wellknown as potent T-cell specific immunosuppressants, and are effectiveagainst graft rejection after organ transplantation. It has beenreported that topical, but not oral, application of FK506 (Yamamoto etal., J. Invest. Dermatol., 1994, 102, 160-164; Jiang et al., J. Invest.Dermatol. 1995, 104, 523-525) and cyclosporin (Iwabuchi et al., J.Dermatol. Sci. 1995, 9, 64-69) stimulates hair growth in adose-dependent manner. One form of hair loss, alopecia areata, is knownto be associated with autoimmune activities; hence, topicallyadministered immunomodulatory compounds are expected to demonstrateefficacy for treating that type of hair loss. The hair growthstimulating effects of FK506 have been the subject of an internationalpatent filing covering FK506 and structures related thereto for hairgrowth stimulation (Honbo et al., EP 0 423 714 A2). Honbo et al.discloses the use of relatively large tricyclic compounds, known fortheir immunosuppressive effects, as hair revitalizing agents.

The hair growth and revitalization effects of FF506 and related agentsare disclosed in many U.S. patents (Goulet et al., U.S. Pat. No.5,258,389; Luly et al., U.S. Pat. No. 5,457,111; Goulet et al., U.S.Pat. No. 5,532,248; Goulet et al., U.S. Pat. No. 5,189,042; and Ok etal., U.S. Pat. No. 5,208,241; Rupprecht et al., U.S. Pat. No. 5,284,840;Organ et al., U.S. Pat. No. 5,284,877). These patents claim FK506related compounds. Although they do not claim methods of hairrevitalization, they disclose the known use of FK506 for effecting hairgrowth. Similar to FK506 (and the claimed variations in the Honbo et al.patent), the compounds claimed in these patents are relatively large.Further, the cited patents relate to immunomodulatory compounds for usein autoimmune related diseases, for which FK506's efficacy is wellknown.

Other U.S. patents disclose the use of cyclosporin and related compoundsfor hair revitalization (Hauer et al., U.S. Pat. No. 5,342,625; Eberle,U.S. Pat. No. 5,284,826; Hewitt et al., U.S. Pat. No. 4,996,193). Thesepatents also relate to compounds useful for treating autoimmune diseasesand cite the known use of cyclosporin and related immunosuppressivecompounds for hair growth.

However, immunosuppressive compounds by definition suppress the immunesystem and also exhibit other toxic side effects. Accordingly, there isa need for non-immunosuppressant, small molecule compounds which areuseful as hair revitalizing compounds.

Hamilton and Steiner disclose in U.S. Pat. No. 5,614,547 novelpyrrolidine carboxylate compounds which bind to the immunophilin FKBP12and stimulate nerve growth, but which lack immunosuppressive effects.Unexpectedly, it has been discovered that these non-immunosuppressantcompounds promote hair growth with an efficacy similar to FK506. Yettheir novel small molecule structure and non-immunosuppressiveproperties differentiate them from FK50 and related immunosuppressivecompounds found in the prior art.

SUMMARY OF THE INVENTION

The present invention relates to a method for treating alopecia orpromoting hair growth in an animal, which comprises administering tosaid animal an effective amount of a heterocyclic thioester or ketone.

The present invention further relates to a pharmaceutical compositionwhich comprises:

-   -   (i) an effective amount of heterocyclic thioesters or ketones        for treating alopecia or promoting hair growth in an animal; and    -   (ii) a pharmaceutically acceptable carrier.

The heterocyclic thioesters and ketones used in the inventive methodsand pharmaceutical compositions have an affinity for FKBP-typeimmunophilins, particularly FKBP12, and do not exert any significantimmunosuppressive activity.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a photograph of C57 Black 6 mice before being shaved for thehair regeneration experiment.

FIG. 2 is a photograph of mice treated with a vehicle after six weeks.FIG. 2 shows that less than 3% of the shaved area is covered with newhair growth when the vehicle (control) is administered.

FIG. 3 is a photograph of mice treated with 10 μM of GPI 1046, a relatednon-immunosuppressive neuro-immunophilin FKBP ligand, after six weeks.FIG. 3 shows the remarkable effects of non-immunosuppressiveneuroimmunophilin FKBP ligands, wherein 90% of the shaved area iscovered with new hair growth.

FIG. 4 is a photograph of mice treated with 30 μM of GPI 1046 after sixweeks. FIG. 4 shows the remarkable ability of non-immunosuppressiveneuroimmunophilin FKBP ligands to achieve, essentially, complete hairregrowth in the shaved area.

FIG. 5 is a bar graph depicting the relative hair growth indices for C57Black 6 mice treated with a vehicle, FK506, and variousnon-immunosuppressive neuroimmunophilin FKBP ligands, including GPI1389, 1511, and 1234, 14 days after treatment with each identifiedcompound. FIG. 5 demonstrates the remarkable early hair growth promotedby a wide variety of non-immunosuppressive neuroimmunophilin FKBPligands.

DETAILED DESCRIPTION OF THE INVENTION Definitions

“Alopecia” refers to deficient hair growth and partial or complete lossof hair, including without limitation androgenic alopecia (male patternbaldness), toxic alopecia, alopecia senilis, alopecia areata, alopeciapelada and trichotillomania. Alopecia results when the pilar cycle isdisturbed. The most frequent phenomenon is a shortening of the hairgrowth or anagen phase due to cessation of cell proliferation. Thisresults in an early onset of the catagen phase, and consequently a largenumber of hairs in the telogen phase during which the follicles aredetached from the dermal papillae, and the hairs fall out. Alopecia hasa number of etiologies, including genetic factors, aging, local andsystemic diseases, febrile conditions, mental stresses, hormonalproblems, and secondary effects of drugs.

“GPI 1605” refers to a compound of formula

“GPI 1046” refers to 3-(3-pyridyl)-1-propyl(2s)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, acompound of formula

“GPI 1312” refers to a compound of formula

“GPI 1572” refers to a compound of formula

“GPI 1389” refers to a compound of formula

“GPI 1511” refers to a compound of formula

“GPI 1234” refers to a compound of formula

“Isomers” refer to different compounds that have the same molecularformula. “Stereoisomers” are isomers that differ only in the way theatoms are arranged in space. “Enantiomers” are a pair of stereoisomersthat are non-superimposable mirror images of each other.“Diastereoisomers” are stereoisomers which are not mirror images of eachother. “Racemic mixture” means a mixture containing equal parts ofindividual enantiomers. “Non-racemic mixture” is a mixture containingunequal parts of individual enantiomers or stereoisomers.

“Pharmaceutically acceptable salt, ester, or solvate” refers to a salt,ester, or solute of a subject compound which possesses the desiredpharmacological activity and which is neither biologically nor otherwiseundesirable. A salt, ester, or solvate can be formed with inorganicacids such as acetate, adipate, alginate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, citrate, camphorate,camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate,ethanesulfonate, fumarate, glucoheptanoate, gluconate, glycerophosphate,hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, naphthylate, 2-naphthalenesulfonate, nicotinate,oxalate, sulfate, thiocyanate, tosylate and undecanoate. Examples ofbase salts, esters, or solvates include ammonium salts; alkali metalsalts, such as sodium and potassium salts; alkaline earth metal salts,such as calcium and magnesium salts; salts with organic bases, such asdicyclohexylamine salts; N-methyl-D-glucamine; and salts with aminoacids, such as arginine, lysine, and so forth. Also, the basicnitrogen-containing groups can be auarternizea with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chlorides,bromides, and iodides; dialkyl sulfates, such as dimethyl, diethyl,dibutyl, and diamyl sulfates; long chain halides, such as decyl, lauryl,myristyl, and stearyl chlorides, bromides, and iodides; aralkyl halides,such as benzyl and phenethyl bromides; and others. Water or oil-solubleor dispersible products are thereby obtained.

“Pilar cycle” refers to the life cycle of hair follicles, and includesthree phases:

-   -   (1) the anagen phase, the period of active hair growth which,        insofar as scalp hair is concerned, lasts about three to five        years;    -   (2) the catagen phase, the period when growth stops and the        follicle atroohies which, insofar as scalp hair is concerned,        lasts about one to two weeks; and    -   (3) the telogen phase, the rest period when hair progressively        separates and finally falls out which, insofar as scalp hair is        concerned, lasts about three to four months.        Normally 80 to 90 percent of the follicles are in the anagen        phase, less than 1 percent being in the catagen phase, and the        rest being in the telogen phase. In the telogen phase, hair is        uniform in diameter with a slightly bulbous, non-pigmented root.        By contrast, in the anagen phase, hair has a large colored bulb        at its root.

“Promoting hair growth” refers to maintaining, inducing, stimulating,accelerating, or revitalizing the germination of hair.

“Treating alopecia” refers to:

-   -   (i) preventing alopecia in an animal which may be predisposed to        alopecia; and/or    -   (ii) inhibiting, retarding or reducing alopecia; and/or    -   (iii) promoting hair growth; and/or    -   (iv) prolonging the anagen phase of the hair cycle; and/or    -   (v) converting vellus hair to growth as terminal hair. Terminal        hair is coarse, pigmented, long hair in which the bulb of the        hair follicle is seated deep in the dermis. Vellus hair, on the        other hand, is fine, thin, non-pigmented short hair in which the        hair bulb is located superficially in the dermis. As alopecia        progresses, the hairs change from the terminal to the vellus        type.

Methods of the Present Invention

The present invention relates, but is not limited, to a method fortreating alopecia or promoting hair growth in an animal, which comprisesadministering to said animal an effective amount of a heterocyclicthioester or ketone.

The inventive method is particularly useful for treating male patternalopecia, alopecia senilis, alopecia areata, alopecia resulting fromskin-lesions or tumors, alopecia resulting from cancer therapy such aschemotherapy and radiation, and alopecia resulting from systematicdisorders such as nutritional disorders and internal secretiondisorders.

Pharmaceutical Compositions of the Present Invention

The present invention also relates to a pharmaceutical compositioncomprising:

-   -   (i) an effective amount of a heterocyclic thioester or ketone        for treating alopecia or promoting hair growth in an animal; and    -   (ii) a pharmaceutically acceptable carrier.

Heterocyclic Thioesters and Ketones

The heterocyclic thioesters and ketones used in the methods andpharmaceutical compositions of the present invention are low molecularweight, small molecule compounds having an affinity for FKBP-typeimmunophilins, such as FKBP12. When a heterocyclic thioester or ketonebinds to an FKBP-type immunophilin, it has been found to inhibit theprolyl-peptidyl cis-trans isomerase, or rotamase, activity of thebinding protein. Unexpectedly, the compounds have also been found tostimulate hair growth. These compounds are devoid of any significantimmunosuppressive activity. Examples of useful compounds are set forthbelow.

Formula I

The heterocyclic thioester or ketone may be a compound of formula I

or a pharmaceutically acceptable salt, ester, or solvate thereof,wherein:

-   -   A and B, taken together with the nitrogen and carbon atoms to        which they are respecively attached, form a 5-7 membered        saturated or unsaturated heterocyclic ring containing, in        addition to the nitrogen atom, one or more additional O, S, SO,        SO₂, N, NH, or NR₂ heteroatom(s);    -   X is either O or S;    -   Z is either S, CH₂, CHR₁ or CR₁R₃;    -   W and Y are independently O, S, CH₂ or H₂;    -   R₁ and R₃ are independently C₁-C₆ straight or branched chain        alkyl or C₂-C₆ straight or branched chain alkenyl, wherein said        alkyl or alkenyl is substituted with one or more substituent(s)        independently selected from the group consisting of (Ar₁)_(n),        C₁-C₆ straight or branched chain alkyl or C₃-C₆ straight or        branched chain alkenyl substituted with (Ar₁)_(n), C₃-C₈        cycloalkyl, C₁-C₆ straight or branched chain alkyl or C₂-C₆        straight or branched chain alkenyl substituted with C₃-C₈        cycloalkyl, and Ar₂;    -   n is 1 or 2;    -   R₂ is either C₁-C₉ straight or branched chain alkyl, C₂-C₉        straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇        cycloalkenyl, or Ar₁, wherein said alkyl, alkenyl, cycloalkyl or        cycloalkenyl is either unsubstituted or substituted with one or        more substituent(s) independently selected from the group        consisting of C₁-C₄ straight or branched chain alkyl, C₂-C₄        straight or branched chain alkenyl, and hydroxy; and    -   Ar and Ar₂ are independently an alicyclic or aromatic, mono-,        bi- or tricyclic, carbo- or heterocyclic ring, wherein said ring        is either unsubstituted or substituted with one or more        substituent(s) independently selected from the group including,        but no limited to, halo, hydroxyl, nitro, trifluoromethyl, C₁-C₆        straight or branched chain alkyl, C₂-C₆ straight or branched        chain alkenyl, C₁-C₄ alkoxy, C₂-C₄ alkenyloxy, phenoxy,        benzyloxy, and amino; wherein the individual ring size is 5-8        members; and wherein the heterocyclic ring contains 1-6        heteroatom(s) independently selected from the group consisting        of O, N, and S.

Useful carbo- and heterocyclic rings include without limitation phenyl,benzyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, indolyl,isoindolyl, indolinyl, benzofuranyl, benzothiophenyl, indazolyl,benzimidazolyl, benzthiazolyl, tetrahydrofuranyl, tetrahydropyranyl,pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl,quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinolizinyl, furyl,thiophenyl, imidazolyl, oxazolyl, benzoxazolyl, thiazolyl, isoxazolyl,isotriazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl, trithianyl, indolizinyl, pyrazolyl,pyrazolinyl, pyrazolidinyl, thienyl, tetrahydroisoquinolinyl,cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl,pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, andphenoxazinyl.

In a preferred embodiment of formula I, the heterocyclic thioester orketone is selected from the group consisting of GPI 1389, of the formula

GPI 1511, of the formula

and GPI 1234, of the formula

Formula II

The heterocyclic thioester or ketone may also be a compound of formulaII

or a pharmaceutically acceptable salt, ester, or solvate thereof,wherein:

-   -   n is 1 or 2;    -   X is O or S;    -   Z is selected from the group consisting of S, CH₂, CHR₁, and        CR₁R₃;    -   R₁ and R₃ are independently selected from the group consisting        of C₁-C₅ straight or branched chain alkyl, C₂-C₅ straight or        branched chain alkenyl, and Ar₁, wherein said alkyl, alkenyl or        Ar₁ is unsubstituted or substituted with one or more        substituent(s) independently selected from the group consisting        of halo, nitro, C₁-C₆ straight or branched chain alkyl, C₂-C₆        straight or branched chain alkenyl, hydroxy, C₁-C₄ alkoxy, C₂-C₄        alkenyloxy, phenoxy, benzyloxy, amino, and Ar₁;    -   R₂ is selected from the group consisting of C₁-C₉ straight or        branched chain alkyl, C₂-C₉ straight or branched chain alkenyl,        C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, and Ar₁; and    -   Ar₁ is phenyl, benzyl, pyranyl, fluorenyl, thioindolyl or        naphthyl, wherein said Ar₁ is unsubstituted or substituted with        one or more substituent(s) independently selected from the group        consisting of halo, trifluoromethyl, hydroxy, nitro, C₁-C₆        straight or branched chain alkyl, C₂-C₆ straight or branched        chain alkenyl, C₁-C₄ alkoxy, C₂-C₄ alkenyloxy, phenoxy,        benzyloxy, and amino.

Preferred compounds of formula II are presented in TABLE I. TABLE I No.n X Z R₁ R₂ 1 1 O CH₂ 3-Phenylpropyl 1,1-Dimethylpropyl 2 1 O CH₂3-(3-Pyridyl)propyl 1,1-Dimethylpropyl 3 1 O CH₂ 3-Phenylpropyltert-Butyl 4 1 O CH₂ 3-(3-Pyridyl)propyl tert-Butyl 5 1 O CH₂3-(3-Pyridyl)propyl Cyclohexyl 6 1 O CH₂ 3-(3-Pyridyl)propyl Cyclopentyl7 1 O CH₂ 3-(3-Pyridyl)propyl Cycloheptyl 8 1 O CH₂ 2-(9-Fluorenyl)ethyl1,1-Dimethylpropyl 9 1 O S 2-Phenethyl 1,1-Dimethylpropyl 10 2 O S2-Phenethyl 1,1-Dimethylpropyl 11 1 O S Methyl(2-thioindole)1,1-Dimethylpropyl 12 1 O S 2-Phenethyl Cyclohexyl 13 2 O S 2-Phenethyltert-Butyl 14 2 O S 2-Phenethyl Phenyl 15 1 O CH₂ 3-(4-1,1-Dimethylpropyl Methoxyphenyl)propyl 16 2 O CH₂ 4-(4-1,1-Dimethylpropyl Methoxyphenyl)butyl 17 2 O CH₂ 4-Phenylbutyl1,1-Dimethylpropyl 18 2 O CH₂ 4-Phenylbutyl Phenyl 19 2 O CH₂4-Phenylbutyl Cyclohexyl 20 1 S CH₂ 3-Phenylpropyl 1,1-Dimethylpropyl 211 S S 2-Phenethyl 1,1-Dimethylpropyl 22 2 S CH₂ 3-Phenylpropyl1,1-Dimethylpropyl 23 2 S S 2-Phenethyl 1,1-Dimethylpropyl 24 2 O CHR₁3-Phenylpropyl 1,1-Dimethylpropyl 25 2 O CHR₁ 3-Phenylpropyl Cyclohexyl26 2 O CHR₁ 3-Phenylpropyl Phenyl 27 2 O CHR₁ 3-Phenylpropyl3,4,5-Trimethoxy- phenyl 28 1 O S 2-Phenethyl Cyclopentyl 29 2 O S3-Phenylpropyl tert-Butyl 30 1 O S 3-Phenylpropyl 1,1-Dimethylpropyl 311 O S 3-(3-Pyridyl)propyl 1,1-Dimethylpropyl 32 1 O S 3-PhenylpropylCyclohexyl 33 1 O S 4-Phenylbutyl Cyclohexyl 34 1 O S 4-Phenylbutyl1,1-Dimethylpropyl 35 1 O S 3-(3-Pyridyl)propyl Cyclohexyl 36 1 O S3,3-Diphenylpropyl 1,1-Dimethylpropyl 37 1 O S 3,3-DiphenylpropylCyclohexyl 38 1 O S 3-(4- 1,1-Dimethylpropyl Methoxyphenyl)propyl 39 2 OS 4-Phenylbutyl tert-Butyl 40 2 O S 1,5-Diphenylpentyl1,1-Dimethylpropyl 41 2 O S 1,5-Diphenylpentyl Phenyl 42 2 O S 3-(4-1,1-Dimethylpropyl Methoxyphenyl)propyl 43 2 O S 3-(4- PhenylMethoxyphenyl)propyl 44 2 O S 3-(1-Naphthyl)propyl 1,1-Dimethylpropyl 451 O S 3,3-Di(4-fluoro)phenyl- 1,1-Dimethylpropyl propyl 46 1 O S4,4-Di(4-fluoro)phenyl- 1,1-Dimethylpropyl butyl 47 1 O S3-(1-Naphthyl)propyl 1,1-Dimethylpropyl 48 1 O S 2,2-Diphenylethyl1,1-Dimethylpropyl 49 2 O S 2,2-Diphenylethyl 1,1-Dimethylpropyl 50 2 OS 3,3-Diphenylpropyl 1,1-Dimethylpropyl 51 1 O S 3-(4-{Trifluoromethyl}-1,1-Dimethylpropyl phenyl)propyl 52 1 O S 3-(2-Naphthyl)propyl1,1-Dimethylpropyl 53 2 O S 3-(1-Naphthyl)propyl 1,1-Dimethylpropyl 54 1O S 3-(3- 1,1-Dimethylpropyl Chloro)phenylpropyl 55 1 O S3-(3-{Trifluoromethyl}- 1,1-Dimethylpropyl phenyl)propyl 56 1 O S3-(2-Biphenyl)propyl 1,1-Dimethylpropyl 57 1 O S3-(2-Fluorophenyl)propyl 1,1-Dimethylpropyl 58 1 O S3-(3-Fluorophenyl)propyl 1,1-Dimethylpropyl 59 2 O S 4-Phenylbutyl1,1-Dimethylpropyl 60 2 O S 3-Phenylpropyl 1,1-Dimethylpropyl 61 1 O S3-(2- 1,1-Dimethylpropyl Chloro)phenylpropyl 62 2 O S 3-(3-1,1-Dimethylpropyl Chloro)phenylpropyl 63 2 O S 3-(2-Fluoro)phenylpropyl1,1-Dimethylpropyl 64 2 O S 3-(3-Fluoro)phenylpropyl 1,1-Dimethylpropyl65 1 O S 3-(2,5- 1,1-Dimethylpropyl Dimethoxyphenyl)- propyl 66 1 O CH₂3-Phenylpropyl Cyclohexyl 67 1 O CH₂ 3-Phenylethyl tert-Butyl 68 2 O CH₂4-Phenylbutyl Cyclohexyl 69 2 O CHR₁ 2-Phenylethyl tert-Butyl 70 1 O CH₂3,3-Di(4-fluorophenyl)- 1,1-Dimethylpropyl propyl 71 2 O CH₂3-Phenylpropyl 1,1-Dimethylpropyl

Preferred compounds of TABLE I are named as follows:

-   1    (2S)-2-({1-Oxo-5-phenyl}-pentyl-1-(3,3-dimethyl-1,2-dioxopentyl)pyrrolidine-   2    3,3-Dimethyl-1-[(2S)-2-(5-(3-pyridyl)pentanoyl)-1-pyrrolidine]-1,2-pentanedione-   3    (2S)-2-({1-Oxo-4-phenyl}-butyl-1-(3,3-dimethyl-1,2-dioxobutyl)pyrrolidine-   9 2-Phenyl-1-ethyl    (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate-   10 2-Phenyl-1-ethyl    1-(3,3-dimethyl-1,2-dioxopentyl)-2-piperidinecarbothioate-   11 (3-Thioindolyl)methyl    (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate-   12 2-Phenyl-1-ethyl    (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate-   14 2-Phenyl-1-ethyl    1-(2-phenyl-1,2-dioxoethyl)-2-piperidinecarbothioate-   28 2-Phenyl-1-ethyl    (2S)-1-(1-cyclopentyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate-   29 3-Phenyl-1-propyl    1-(3,3-dimethyl-1,2-dioxobutyl)-2-piperidinecarbothioate-   30 3-Phenyl-1-propyl    (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate-   31 3-(3-Pyridyl)-1-propyl    (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate-   32 3-Phenyl-1-propyl    (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate-   33 4-Phenyl-1-butyl    (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate-   34 4-Phenyl-1-butyl    (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate-   35 3-(3-Pyridyl)-1-propyl    (2s)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate 36    3,3-Diphenyl-1-propyl    (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate-   37 3,3-Diphenyl-1-propyl    (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate-   38 3-(para-Methoxyphenyl)-1-propyl    (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2 -pyrrolidinecarbothioate-   39    4-Phenyl-1-butyl-1-(1,2-dioxo-3,3-dimethylbutyl)-2-piperidinecarbothioate-   40 1,5-Diphenyl-3-pentyl    1-(3,3-dimethyl-1,2-dioxopentyl)-2-piperidinecarbothioate-   41 1,5-Diphenyl-3-mercaptopentyl    1-(3-phenyl-1,2-dioxoethyl)-2-piperidinecarbothioate-   42 3-(para-Methoxyphenyl)-1-propyl    1-(1,2-dioxo-3,3-dimethylpentyl)piperidine-2-carbothioate-   43 3-(para-Methoxyphenyl)-1-propyl    1-(2-phenyl-1,2-dioxoethyl)piperidine-2-carbothioate-   44 3-(1-Naphthyl)-1-propyl    1-(3,3-dimethyl-1,2-dioxopentyl)piperidine-2-carbothioate-   45 3,3-Di(para-fluoro)phenyl-1-propyl    (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate-   46 4,4-Di(para-fluorophenyl)butyl    1-(3,3-dimethyl-9-oxopentanoyl)-2-pyrrolidinecarbothioate-   47 3-(1-Naphthyl)propyl    (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate-   48 2,2-Diphenylethyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)tetrahydro    1H-2-pyrrolidinecarbothioate-   49 2,2-Diphenylethyl    (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate-   50 3,3-Diphenylpropyl    1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate-   51 3-[4-(Trifluoromethyl)phenyl]propyl    (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate-   52 3-(2-Naphthyl)propyl    (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate-   53 3-(2-Naphthyl)propyl    (2R,S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate-   54 3-(3-Chlorophenyl)propyl    (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate-   55 3-[3-(Trifluoromethyl)phenyl]propyl    (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate-   56 3-(1-Biphenyl)propyl    (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate-   57 3-(2-Fluorophenyl)propyl    (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate-   58 3-(3-Fluorophenyl)propyl    (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate-   59 4-Phenylbutyl    1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate-   60 3-Phenylpropyl    1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate-   61 3-(2-Chlorophenyl)propyl    (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate-   62 3-(2-Chlorophenyl)propyl    1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate-   63 3-(2-Fluorophenyl)propyl    1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate-   64 3-(3-Fluorophenyl)propyl    1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate-   65 3-(3,4-Dimethoxyphenyl)propyl    (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate-   66    (2S)-2-({1-Oxo-4-phenyl}-butyl-1-(2-Cyclohexyl-1,2-dioxoethyl)pyrrolidine-   67    2-({1-Oxo-4-phenyl-butyl-1-(3,3-dimethyl-1,2-dioxobutyl)pyrrolidine-   68    2-({1-Oxo-6-phenyl}-nexyl-1-(2-Cyclohexyl-1,2-dioxoethyl)piperidine-   69    2-({1-Oxo-[2-(2′-phenyl}ethyl]-4-phenyl}-butyl-1-(3,3-dimethyl-1,2-dioxobutyl)piperidine-   70    1-{(2S)-2-[5,5-di(4-Fluorophenyl)pentanoyl]-2-pyrrolidine}-3,3-dimethyl-1,2-pentanedione-   71 3,3-Dimethyl-1-[2-(4-phenylpentanoyl)piperidino]-1,2-pentanedione

In another preferred embodiment of formula II, the heterocyclicthioester or ketone is selected from the group consisting of GPI 1389,of the formula

GPI 1511, of the formula

and GPI 1234, of the formula

Formula III

Furthermore, the heterocyclic thioester or ketone may be a compound offormula III

or a pharmaceutically acceptable salt, ester, or solvate thereof,wherein:

-   -   A, B, and C are independently CH₂, O, S, SO, SO₂, NH or NR₂;    -   X is O or S;    -   Z is S, CH₂, CHR₁ or CR₁R₃;    -   R₁ and R₃ are independently C₁-C₆ straight or branched chain        alkyl or C₂-C₆ straight or branched chain alkenyl, wherein said        alkyl or alkenyl is substituted with one or more substituent(s)        independently selected from the group consisting of (Ar₁)_(n),        C₃-C₈ straight or branched chain alkyl or C₂-C₆ straight or        branched chain alkenyl substituted with (Ar₁)_(n), C₃-C₈        cycloalkyl, C₁-C₆ straight or branched chain alkyl or C₂-C₆        straight or branched chain alkenyl substituted with C₃-C₈        cycloalkyl, and Ar₂;    -   n is 1 or 2;    -   R₂ is either C₁-C₉ straight or branched chain alkyl, C₂-C₉        straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇        cycloalkenyl or Ar₁, wherein said alkyl, alkenyl, cycloalkyl or        cycloalkenyl is either unsubstituted or substituted with one or        more substituent(s) independently selected from the group        consisting of C₁-C₄ straight or branched chain alkyl, C₂-C₄        straight or branched chain alkenyl, and hydroxyl; and    -   Ar₁ and Ar₂ are independently an alicyclic or aromatic, mono-,        bi- or tricyclic, carbo- or heterocyclic ring, wherein said ring        is either unsubstituted or substituted with one or more        substituent(s) independently selected from the group including,        but not limited to, halo, hydroxyl, nitro, trifluoromethyl,        C₁-C₆ straight or branched chain alkyl, C₂-C₆ straight or        branched chain alkenyl, C₁-C₄ alkoxy, C₂-C₄ alkenyloxy, phenoxy,        benzvloxy, and amino; wherein the individual ring size is 5-8        members; and wherein the heterocyclic ring contains 1-6        heteroatom(s) independently selected from the group consisting        of O, N, and S.

Preferred compounds of formula III are presented in TABLE II. TABLE IINo. A B C X Z R₁ R₂ 72 CH₂ S CH₂ O S 2-phenethyl 1,1-dimethyl- propyl 73CH₂ S CH₂ O CH₂ 3-phenylpropyl 1,1-dimethyl- propyl 74 CH₂ CH₂ NH O S2-phenethyl 1,1-dimethyl- propyl 75 CH₂ S CH₂ S S 2-phenethyl1,1-dimethyl- propyl

In another Dreferred embodiment of formula III, the heterocyclicthioester or ketone is selected from the group consisting of GPI 1389,of the formula

GPI 1511, of the formula

and GPI 1234, of the formula

Formula IV

Alternatively, the heterocyclic thioester or ketone may be a compound offormula IV

or a pharmaceutically acceptable salt, ester, or solvate thereof,wherein:

-   -   A, B, C and D are independently CH₂, O, S, SO, SO₂, NH or NR₂;    -   X is O or S;    -   Z is S, CH₂, CHR₁ or CR₁R₃;    -   R₁ and R₃ are independently C₁-C₆ straight or branched chain        alkyl or C₂-C₆ straight or branched chain alkenyl, wherein said        alkyl or alkenyl is substituted with one or more substituent(s)        independently selected from the group consisting of (Ar₁)_(n),        C₁-C₄ straight or branched chain alkyl or C₂-C₆ straight or        branched chain alkenyl substituted with (Ar₁)_(n), C₃-C₈        cycloalkyl, C₁-C₆ straight or branched chain alkyl or C₂-C₆        straight or branched chain alkenyl substituted with C₃-C₈        cycloalkyl, and Ar₂;    -   n is 1 or 2;    -   R₂ is either C₁-C₉ straight or branched chain alkyl, C₂-C₉        straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇        cycloalkenyl or Ar₁, wherein said alkyl, alkenyl, cycloalkyl or        cycloalkenyl is either unsubstituted or substituted with one or        more substituent(s) independently selected from the group        consisting of C₃-C₈ cycloalkyl, C₁-C₄ straight or branched chain        alkyl, C₂-C₄ straight or branched chain alkenyl, and hydroxyl;        and    -   Ar₁ and Ar₂ are independently an alicyclic or aromatic, mono-,        bi- or tricyclic, carbo- or heterocyclic ring, wherein said ring        is either unsubstituted or substituted with one or more        substituent(s) independently selected from the group including,        but not limited to, halo, hydroxyl, nitro, trifluoromethyl,        C₂-C₆ straight or branched chain alkyl, C₂-C₆ straight or        branched chain alkenyl, C₁-C₄ alkoxy, C₂-C₄ alkenyloxy, phenoxy,        benzyloxy, and amino; wherein the individual ring size is 5-8        members; and wherein the heterocyclic ring contains 1-6        heteroatom(s) independently selected from the group consisting        of O, N, and S.

Preferred compounds of formula IV are presented in TABLE III. TABLE IIINo. A B C D X Z R₁ R₂ 76 CH₂ CH₂ O CH₂ O CH₂ 3- 1,1-di- phenylpropylmethylpropyl 77 CH₂ CH₂ O CH₂ O S 2- 1,1-di- phenethyl methylpropyl 78CH₂ CH₂ S CH₂ O CH₂ 3- 1,1-di- phenylpropyl methylpropyl 79 CH₂ CH₂ SCH₂ O S 2- 1,1-di- phenethyl methylpropyl

Formula V

Alternatively, the heterocyclic thioester or ketone may be a compound offormula V

or a pharmaceutically acceptable salt, ester, or solvate thereof,wherein:

-   -   V is C, N, or S;    -   A and B, taken together with V and the carbon atom to which they        are respectively attached, form a 5-7 membered saturated or        unsaturated heterocyclic ring containing, in addition to V, one        or more heteroatom(s) independently selected from the group        consisting O, S, SO, SO₂, N, NH, and NR₄;    -   R₄ is either C₁-C₉ straight or branched chain alkyl, C₂-C₉        straight or branched chain alkenyl, C₃-C₉ cycloalkyl, C₅-C₇        cycloalkenyl, or Ar₃, wherein R₄ is either unsubstituted or        substituted with one or more substituent(s) independently        selected from the group consisting of halo, haloalkyl, carbonyl,        carboxy, hydroxy, nitro, trifluoromethyl, C₁-C₆ straight or        branched chain alkyl, C₂-C₆ straight or branched chain alkenyl,        C₁-C₄ alkoxy, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, thioalkyl,        alkylthio, sulfhydryl, amino, alkylamino, aminoalkyl,        aminocarboxyl, and Ar₄;    -   Ar₃ and Ar₄ are independently an alicyclic or aromatic, mono-,        bi- or tricyclic, carbo- or heterocyclic ring; wherein the        individual ring size is 5-8 members; wherein said heterocyclic        ring contains 1-6 heteroatom(s) independently selected from the        group consisting of O, N, and S; and    -   R₁, R₂, W, X, Y, and Z are as defined in Formula I above.

All the compounds of Formulas I-V possess asymmetric centers and thuscan be produced as mixtures of stereoisomers or as individual R- andS-stereoisomers. The individual stereoisomers may be obtained by usingan optically active starting material, by resolving a racemic ornon-racemic mixture of an intermediate at some appropriate stage of thesynthesis, or by resolving the compounds of Formulas I-V. It isunderstood that the compounds of Formulas I-V encompass individualstereoisomers as well as mixtures (racemic and non-racemic) ofstereoisomers. Preferably, S-stereoisomers are used in thepharmeceutical compositions and methods of the present invention.

Affinity for FKBP12

The compounds used in the inventive methods and pharmaceuticalcompositions have an affinitv for the FK506 binding protein,particularly FKBP12. The inhibition of the prolyl peptidyl cis-transisomerase activity of FKBP may be measured as an indicator of thisaffinity.

K_(i) Test Procedure

Inhibition of the peptidyl-prolyl isomerase (rotamase) activity of thecompounds used in the inventive methods and pharmaceutical compositionscan be evaluated by known methods described in the literature (Hardinget al., Nature, 1989, 341:758-760; Holt et al. J. Am. Chem. Soc.,115:9923-9938). These values are obtained as apparent K_(i)'s and arepresented for representative compounds in TABLE IV.

The cis-trans isomerization of an alanine-proline bond in a modelsubstrate, N-succinyl-Ala-Ala-Pro-Phe-p-nitroanilide, is monitoredspectrophotometrically in a chymotrypsin-coupled assay, which releasespara-nitroanilide from the trans form of the substrate. The inhibitionof this reaction caused by the addition of different concentrations ofinhibitor is determined, and the data is analyzed as a change infirst-order rate constant as a function of inhibitor concentration toyield the apparent K_(i) values.

In a plastic cuvette are added 950 mL of ice cold assay buffer (25 mMHEPES, pH 7.8, 100 mM NaCl), 10 mL of FKBP (2.5 mM in 10 mM Tris-Cl pH7.5, 100 mM NaCl, 1 mM dithiothreitol), 25 mL of chymotrypsin (50 mg/mlin 1 mM HCl) and 10 mL of test compound at various concentrations indimethyl sulfoxide. The reaction is initiated by the addition of 5 mL ofsubstrate (succinyl-Ala-Phe-Pro-Phe-para-nitroanilide, 5 mg/mL in 2.35mM LiCl in trifluoroethanol).

The absorbance at 390 nm versus time is monitored for 90 seconds using aspectrophotometer and the rate constants are determined from theabsorbance versus time data files. TABLE IV In Vitro Test Results -Formulas I to V Compound K_(i) (nM) 1 31 2 210 3 85 9 104 10 12 11 29912 442 14 313 28 108 29 59 30 11 31 8.7 32 362 33 1698 34 34 35 62 36 737 68 38 8.9 39 347 40 1226 41 366 42 28 43 259 44 188 45 31 46 757 4721 48 127 49 1334 50 55 51 33 52 6 53 261 54 37 55 30 56 880 57 57 58 7959 962 60 90 61 139 62 196 63 82 64 163 65 68 66 306 67 177 68 284 69 4970 457 71 788

Route of Administration

To effectively treat alopecia or promote hair growth, the compounds usedin the inventive methods and pharmaceutical compositions must readilyaffect the targeted areas. For these purposes, the compounds arepreferably administered topically to the skin.

For topical application to the skin, the compounds can be formulatedinto suitable ointments containing the compounds suspended or dissolvedin, for example, mixtures with one or more of the following: mineraloil, liquid petrolatum, white petrolatum, propylene glycol,polyoxyethylene polyoxypropylene compound, emulsifying wax and water.Alternatively, the compounds can be formulated into suitable lotions orcreams containing the active compound suspended or dissolved in, forexample, a mixture of one or more of the following: mineral oil,sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearylalcohol, 2-octyldodecanol, benzyl alcohol and water.

Other routes of administration known in the pharmaceutical art are alsocontemplated by this invention.

Dosage

Dosage levels on the order of about 0.1 mg to about 10,000 mg of theactive ingredient compound are useful in the treatment of the aboveconditions, with preferred levels of about 0.1 mg to about 1,000 mg. Thespecific dose level for any particular patient will vary depending upona variety of factors, including the activity of the specific compoundemployed; the age, body weight, general health, sex and diet of thepatient; the time of administration; the rate of excretion; drugcombination; the severity of the particular disease being treated; andthe form of administration. Typically, in vitro dosage-effect resultsprovide useful guidance on the proper doses for patient administration.Studies in animal models are also helpful. The considerations fordetermining the proper dose levels are well known in the art.

The compounds can be administered with other hair revitalizing agents.Specific dose levels for the other hair revitalizing agents will dependupon the factors previously stated and the effectiveness of the drugcombination.

EXAMPLES

The following examples are illustrative of the present invention and arenot intended to be limitations thereon. Unless otherwise indicated, allpercentages are based upon 100% by weight of the final composition.

Example 1 Synthesis of(2S)-2-({1-oxo-5-phenyl-pentyl-1-(3,3-dimethyl-1,2-dioxopentyl)pyrrolidine(Compound 1) (2S)-2-(1-oxo-4-phenyl)butyl-N-benzylpyrrolidine

1-chloro-4-phenylbutane (1.78 g; 10.5 mmol) in 20 mL of THF was added to0.24 g (10 mmol) of magnesium turnings in 50 mL of refluxina THF. Afterthe addition was complete, the mixture was refluxed for an additional 5hours, and then added slowly to a refluxing solution ofN-benzyl-L-proline ethyl ester (2.30 g (10 mmol) in 100 mL of THF. After2 hours of further reflux, the mixture was cooled and treated with 5 mLof 2 N HCl. The reaction mixture was diluted with ether (100 mL) andwashed with saturated NaHCO₃, water and brine. The organic phase wasdried, concentrated and chromatographed, eluting with 5:1 CH₂C₂:EtOAc toobtain 2.05 g (64%) of the ketone as an oil. ¹H NMR (CDCl₃; 300 MHz) :1.49-2.18 (m, 8H); 2.32-2.46 (m, 1H); 2.56-2.65 (m, 2H); 2.97-3.06 (m,1H); 3.17-3.34 (m, 1H); 3.44-3.62 (m, 1H); 4.02-4.23 (m, 2H); 7.01-7.44(m, 10H).

(2S)-2-(1-oxo-4-phenyl)butylpyrrolidine

The ketone compound (500 mg) and palladium hydroxide (20% on carbon, 50mg) was hydrogenated at 40 psi in a Paar shaker overnight. The catalystwas removed by filtration and the solvent was removed in vacuo. The freeamine was obtained as a yellow oil (230 mg; 100%). ¹H NMR (CDCl₃; 300MHz) : 1.75-2.34 (m, 10H); 2.55 (m, 2H); 2.95 (dm, 1H); 3.45-3.95 (m,1H); 4.05 (m, 1H); 7.37 (m, 5H).

(2S)-2-(1-oxo-4-phenyl)butyl-1-(1,2-dioxo-2-methoxyethyl)pyrrolidine

To a solution of (2S)-2-(1-oxo-4-phenyl)butylpyrrolidine (230 mg; 1.0mmol) in CH₂Cl₂(20 mL) at 0° C. was added dropwise methyloxalyl chloride(135 mg; 1.1 mmol). After stirring at 0° C. for 3 hours, the reactionwas quenched with saturated NH₄ Cl and the organic phase was washed withwater and brine and dried and concentrated. The crude residue waspurified on a silica gel column, eluding with 20:1 CH₂Cl₂:EtOAc toobtain 300 mg of the oxamate as a clear oil (98%). ¹H NMR (CDCl₃; 300MHz): 1.68 (m, 4H); 1.91-2.38 (m, 4H) ; 2.64 (t, 2H) ; 3.66-3.80 (m, 2H)3.77, 3.85 (s, 3H total); 4.16 (m, 2H); 4.90 (m, 1H); 7.16 (m, 3H) ;7.27 (m, 2H)

(2S)-2-({1-oxo-5-phenyl}-pentyl-1-(3,3-dimethyl-1,2-dioxopentyl)pyrrolidine(1)

To a solution of the oxamate above (250 mg; 0.79 mmol) in anhydrousether (15 mL), cooled to −78° C., was added 1,1-dimethylpropyl-magnesiumchloride (0.8 mL of a 1.0 M solution in ether; 0.8 mmol). After stirringthe resulting mixture at −78° C. for 2 hours, the reaction was quenchedby the addition of 2 mL of saturated NH₄Cl, followed by 100 mL of EtOAc.The organic phase was washed with brine, dried, concentrated, andpurified on a silica gel column, eluting with 50:1 CH₂Cl₂:EtOAc.Compound 1 was obtained as a clear oil, 120 mg. ¹H NMR (CDCl₃, 300 MHz):δ 0.87 (t, 3H, J=7.5); 1.22 (s, 3H); 1.25 (s, 3H) ; 1.67 (m, 4H) ;1.70-2.33 (m, 6H); 2.61 (t, 2H, J=7.1); 3.52 (m, 2H); 4.17 (t, 2H,J=6.2); 4.52 (m, 1H); 7.16-7.49 (m, 5H). Analysis calculated forC₂₂H₃₁NO₃—H₂O: C, 70.37; H, 8.86; N, 3.73. Found: 70.48; H, 8.35; N,3.69.

Example 2 Synthesis of 2-phenyl-1-ethyl1-(3,3-dimethyl-1,2-dioxopentyl)-2-piperidinecarbothioate (10)Methyl(2S) -1(1,2-dioxo-2-methoxvethvl)-2-pyrrolidinecarboxylate

A solution of L-proline methyl ester hydrochloride (3.08 g; 18.60 mmol)in dry methylene chloride was cooled to 0° C. and treated withtriethylamine (3.92 g; 38.74 mmol; 2.1 eq). After stirring the formedslurry under a nitrogen atmosphere for 15 min, a solution of methyloxalyl chloride (3.20 g; 26.12 mmol) in methylene chloride (45 mL) wasadded dropwise. The resulting mixture was stirred at 0° C. for 1.5 hour.After filtering to remove solids, the organic phase was washed withwater, dried over MgSO₄ and concentrated. The crude residue was purifiedon a silica gel column, eluting with 50% ethyl acetate in hexane, toobtain 3.52 g (88%) of the product as a reddish oil. Mixture ofcis-trans amide rotamers; data for trans rotamer given. ¹H NMR (CDCl₃) δ1.93 (dm, 2H) ; 2.17 (m, 2H) ; 3.62 (m, 2H) ; 3.71 (s, 3H) 3.79, 3.84(s, 3H total); 4.86 (dd, 1H, J=8.4, 3.3).

Methyl (2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-pyrrolidinecarboxylate

A solution of methyl(2S)-1-(1,2-dioxo-2-methoxyethyl)-2-pyrrolidinecarboxylate (2.35 g;10.90 mmol) in 30 mL of tetrahydrofuran (THF) was cooled to −78° C. andtreated with 14.2 mL of a 1.0 M solution of 1,1-dimethylpropylmagnesiumchloride in THF. After stirring the resulting homogeneous mixture at−78° C. for three hours, the mixture was poured into saturated ammoniumchloride (100 mL) and extracted into ethyl acetate. The organic phasewas washed with water, dried, and concentrated, and the crude materialobtained upon removal of the solvent was purified on a silica gelcolumn, eluting with 25% ethyl acetate in hexane, to obtain 2.10 g (75%)of the oxamate as a colorless oil. ¹H NMR (CDCl₃): δ 0.88 (t, 3H); 1.22,1.26 (s, 3H each); 1.75(dm, 2H) ; 1.87-2.10 (m, 3H); 2.23 (m, 1H) ; 3.54(m, 2H) ; 3.76 (s, 3H) ; 4.52 (dm, 1H, J=8.4, 3.4).

(2S)-1-(1,2-dioxo-3 3-dimethyldentyl)-2-pyrrolidine-carboxylic acid

A mixture of methyl(2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-pyrrolidinecarboxylate (2.10 g;8.23 mmol), 1 N LIOH (15 mL), and methanol (50 mL) was stirred at 0° C.for 30 minutes and at room temperature overnight. The mixture wasacidified to pH 1 with 1 N HC_(1,) diluted with water, and extractedinto 100 mL of methylene chloride. The organic extract-was washed withbrine and concentrated to deliver 1.73 g (87%) of snow-white solid whichdid not require further purification. ¹H NMR (CDCl₃): δ 0.87 (t, 3H);1.22, 1.25 (s, 3H each); 1.77 (dm, 2H); 2.02 (m, 2H); 2.17 (m, 1H); 2.25(m, 1H); 3.53 (dd, 2H, J=10.4, 7.3); 4.55 (dd, 1H, J=8.6, 4.1).

2-phenyl-1-ethyl1-(3,3-dimethyl-1,2-dioxonentyl)-2-piperidinecarbothioate (10)

To a solution of(2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-pyrrolidinecarboxylic acid (241mg; 1.0 L mmol) in CH₂Cl₂ (10 mL) was added dicyclohexylcarbo-diimide(226 mg; 1.1 mmol). After stirring the resulting mixture for 5 minutes,the solution was cooled to 0° C. and treated with a solution of phenylmercaptan (138 mg; 1.0 mmol) and 4-dimethylaminopyridine (6 mg) in 5 mlof CH₂Cl₂. The mixture was allowed to warm to room temperature withstirring overnight. The solids were removed by filtration and thefiltrate was concentrated in vacuo; the crude residue was purified byflash chromatography (10:1 hexane:EtOAc) to obtain 302 mg (84%) ofcompound 10 as an oil. ¹H NMR (CDCl₃, 300 MHz): δ 0.85 (t, 3H, J=7.5);1.29 (s, 3H); 1.31 (s, 3H); 1.70-2.32 (m, 6H) ; 2.92 (t, 2H, J=7.4);3.22(t, 2H, J=7.4); 3.58 (m, 2H) ; 4.72 (m, 1H) ; 7.23-7.34 (m, 5H).Analysis calculated for C₂₀H₂₇NO₃S-0.4H₂O: C, 65.15; H, 7.60; N, 3.80.Found: C, 65.41; H, 7.49; N, 3.72.

Example 3 Synthesis of 2-phenyl-1-ethyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate (9)Methyl 1-(1,2-dioxo-2-methoxvethyl)-2-piperidine-carboxylate

A solution of methyl pipecolate hydrochloride (8.50 g; 47.31 mmol) indry methylene chloride (100 mL) was cooled to 0° C. and treated withtriethylamine (10.5 g; 103 mmol; 2.1 eq). After stirring the formedslurry under a nitrogen atmosphere for 15 minutes, a solution of methyloxalyl chloride (8.50 g; 69.4 mmol) in methylene chloride (75 mL) wasadded dropwise. The resulting mixture was stirred at 0° C. for 1,5hours. After filtering to remove solids, the organic phase was washedwith water, dried over MgSO₄ and concentrated. The crude residue waspurified on a silica gel column, eluting with 50% ethyl acetate inhexane, to obtain 9.34 g (86%) of the product as a reddish oil. Mixtureof cis-trans amide rotamers; data for trans rotamer given. ¹H NMR(CDCl₃): δ 1.22-1.45 (m, 2H); 1.67-1.78 (m, 3H); 2.29 (m, 1H) ; 3.33 (m,1H); 3.55 (m, 1H); 3.76 (s, 3H); 3.85, 3.87 (s, 3H total); 4.52 (dd,1H).

Methyl 1-(1,2-dioxo-3,3-dimethylpentyl) -2-piperidine-carboxylate

A solution of methyl1-(1,2-dioxo-2-methoxyethyl)-2-piperidinecarboxylate (3.80 g; 16.57mmol) in 75 mL of tetrahydrofuran (THF) was cooled to −78° C. andtreated with 20.7 mL of a 1.0 M solution of 1,1-dimethyl-propylmagnesiumchloride in THF. After stirring the resulting homogeneous mixture at−78° C. for three hours, the mixture was poured into saturated ammoniumchloride (100 mL) and extracted into ethyl acetate. The organic phasewas washed with water, dried, and concentrated, and the crude materialobtained upon removal of the solvent was purified on a silica gelcolumn, eluting with 25% ethyl acetate in hexane, to obtain 3.32 a (74%)of the oxamate as a colorless oil. ¹H NMR (CDC₁ ₃): δ 0.88 (t, 3H) ;1.21, 1.25 (s, 3H each); 1.35-1.80 (m, 7H); 2.35 (m, 1H); 3.24 (m, 1H);3.41 (m, 1H); 3.76 (s, 3H); 5.32 (d, 1H).

1-(1 ,2-dioxo-3,3-dimethylentyl)-2-piperidine-carboxylic acid

A mixture of methyl1-(1,2-dioxo-3,3-dimethylpentyl)-2-piperidinecarboxylate (3.30 g; 12.25mmol), 1 N LiOH (15 mL), and methanol (60 mL) was stirred at 0° C. for30 minutes and at room temperature overnight. The mixture was acidifiedto pH 1 with 1 N HCl, diluted with water, and extracted into 100 mL ofmethylene chloride. The organic extract was washed with brine andconcentrated to deliver 2.80 g (87%) of snow-white solid which did notrequire further purification. ¹H NMR (CDCl₃): δ 0.89 (t, 3H); 1.21, 1.24(s, 3H each); 1.42-1.85 (m, 7H); 2.35 (m, 1H) 3.22 (d, 1H); 3.42(m, 1H);5.31 (d, 1H).

2-phenyl-1-ethyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate (9)

To a solution of1-(1,2-dioxo-3,3-dimethylpentyl)-2-piperidine-carboxylic acid (255 mg;1.0 mmol) in CH₂Cl₂ (10 mL) was added dicyclohexylcarbodiimide (226 mg;1.1 mmol). After stirring the resulting mixture for 5 minutes, thesolution was cooled to 0° C. and treated with a solution of phenylmercaptan (138 mg; 1.0 mmol) and 4-dimethylaminopyridine (6 mg) in 5 mlof CH₂Cl₂. The mixture was allowed to warm to room temperature withstirring overnight. The solids were removed by filtration and thefiltrate was concentrated in vacuo; the crude residue was purified byflash chromatography (10:1 hexane:EtOAc) to obtain 300 mg (80%) ofcompound 9 as an oil. ¹H NMR (CDCl₃, 300 MHz): d 0.94 (t, 3H, J=7.5);1.27 (s, 3H); 1.30 (s, 3H); 1.34-1.88 (m, 7H); 2.45 (m, 1H); 2.90 (t,2H, J=7.7); 3.26 (t, 2H, J=7.7); 3.27 (m, 1H); 3.38 (m, 1H); 5.34 (m,1H) 7.24-7.36 (m, 5H). Analysis calculated for C₂₁H₂₉NO₃S: C, 67.17; H,7.78; N, 3.73. Found: C, 67.02; H, 7.83; N, 3.78.

Example 4 In Vivo Hair Generation Tests With C₅₇ Black 6 Mice

Experiment A: C₅₇ black 6 mice were used to demonstrate the hairrevitalizing properties of a low molecular weight, small moleculenon-immunosuppressive neuroimmunophilin FKBP ligand, GPI 1046, which isrelated to heterocyclic thioesters and ketones. Referring now to FIGS. 1and 2 of the drawings, C₅₇ black 6 mice, approximately 7 weeks old, hadan area of about 2 inches by 2 inches on their hindquarters shaved toremove all existing hair. Care was taken not to nick or cause abrasionto the underlaying dermal layers. The animals were in anagen growthphase, as indicated by the pinkish color of the skin. Referring now toFIGS. 2, 3 and 4, fou-r animals per group were treated by topicaladministration with 20% propylene glycol vehicle (FIG. 2), 10 AM GPI1046 (FIG. 3) or 30 μM GPI 1046 (FIG. 4) dissolved in the vehicle. Theanimals were treated with vehicle or GPI 1046 every 48 hours (3applications total over the course of 5 days) and the hair growth wasallowed to proceed for 6 weeks. Hair growth was quantitated by thepercent of shaved area covered by new hair growth during this timeperiod.

FIG. 2 shows that animals treated with vehicle exhibited only a smallamount of hair growth in patches or tufts, with less than 3% of theshaved area covered with new growth. In contrast, FIG. 3 shows thatanimals treated with 10 μM GPI 1046 exhibited dramatic hair growth,covering greater than 90% of the shaved area in all animals. Further,FIG. 4 shows that mice treated with 30 μM GPI 1046 exhibited essentiallycomplete hair regrowth and their shaved areas were indistinguishablefrom unshaven C₅₇ black 6 mice.

Experiment B: C₅₇ Black 6 mice were used to demonstrate the hairrevitalizing properties of a variety of low molecular weight, smallmolecule, non-immunosuppressive neuroimmunophilin FKBP ligands,including GPI 1389, 1511, and 1234. C₅₇ Black 6 mice, 55 to/5 days old,had an area of about 2 inches by 2 inches on their hindquarters shavedto remove all existing hair. Care was taken not to nick or causeabrasion to the underlying dermal layers. The animals were in anagengrowth phase when shaved. Five animals per group were treated by topicaladministration with a vehicle, FK506, or one of the low molecularweight, small molecule, non-immunosuppressive neuroimmunophilin FKBPligands (GPI 1605, 1046, 1312, 1572, 1389, 1511, and 1234) at aconcentration of one micromole per milliliter to the shaved area. Theanimals were treated three times per week, and hair growth was evaluated14 days after initiation of treatment. Hair growth was quantitated bythe percent of shaved area covered by new hair growth, as scored by ablinded observer, on a scale of 0 (no growth) to five (complete hairregrowth in shaved area).

FIG. 5 shows that after 14 days, the animals treated with vehicleexhibited the beginning of growth in small tufts. In contrast, animalstreated with one of the low molecular weight, small molecule,non-immunosuppressive neuroimmunophilin FKBP ligands, including GPI1389, 1511, and 1234, exhibited dramatic hair growth.

Example 5

A lotion comprising the following composition may be prepared. (%) 95%Ethanol 80.0 a heterocyclic thioester or ketone as defined 10.0 aboveα-Tocopherol acetate 0.01 Ethylene oxide (40 mole) adducts of hardened0.5 castor oil purified water 9.0 perfume and dye q.s.

Into 95% ethanol are added a heterocyclic thioester or ketone,α-tocopherol acetate, ethylene oxide (40 mole) adducts of hardenedcastor oil, perfume and a dye. The resulting mixture is stirred anddissolved, and purified water is added to the mixture to obtain atransparent liquid lotion.

5 ml of the lotion may be applied once or twice per day to a site havingmarked baldness or alopecia.

Example 6

A lotion comprising the following composition shown may be prepared. (%)95% Ethanol 80.0 a heterocyclic thioester or ketone as defined 0.005above Hinokitol 0.01 Ethylene oxide (40 mole) adducts of hardened 0.5castor oil Purified water 19.0 Perfume and dye q.s.

Into 95% ethanol are added a heterocyclic thioester or ketone,hinokitol, ethylene oxide (40 mole) adducts of hardened castor oil,perfume, and a dye. The resulting mixture is stirred, and purified wateris added to the mixture to obtain a transparent liquid lotion.

The lotion may be applied by spraying once to 4 times per day to a sitehaving marked baldness or alopecia.

Example 7

An emulsion may be prepared from A phase and B phase having thefollowing compositions. (%) (A phase) Whale wax 0.5 Cetanol 2.0Petrolatum 5.0 Squalane 10.0 Polyoxyethylene (10 mole) monostearate 2.0Sorbitan monooleate 1.0 a heterocyclic thioester or ketone as defined0.01 above (B phase) Glycerine 10.0 Purified water 69.0 Perfume, dye,and preservative q.s.

The A phase and the B phase are respectively heated and melted andmaintained at 80° c. Both phases are then mixed and cooled understirring to normal temperature to obtain an emulsion.

The emulsion may be applied by spraying once to four times per day to asite having marked baldness or alopecia.

Example 8

A cream may be prepared from A phase and B phase having the followingcompositions. (%) (A Phase) Fluid paraffin 5.0 Cetostearyl alcohol 5.5Petrolatum 5.5 Glycerine monostearate 33.0 Polyoxyethylene (20 mole)2-octyldodecyl 3.0 ether Propylparaben 0.3 (B Phase) a heterocyclicthioester or ketone as 0.8 defined above Glycerine 7.0 Dipropyleneglycol 20.0 Polyethylene glycol 4000 5.0 Sodium Hexametaphosphate 0.005Purified water 44.895

The A phase is heated and melted, and maintained at 70° c. The B phaseis added into the A phase and the mixture is stirred to obtain anemulsion. The emulsion is then cooled to obtain a cream.

The cream may be applied once to 4 times per day to a site having markedbaldness or alopecia.

Example 9

A liquid comprising the following composition may be prepared. (%)Polyoxyethylene butyl ether 20.0 Ethanol 50.0 a heterocyclic thioesteror ketone as defined 0.001 above Propylene glycol 5.0 Polyoxyethylenehardened castor oil 0.4 derivative (ethylene oxide 80 mole adducts)Perfume q.s. Purified water q.s.

Into ethanol are added polyoxypropylene butyl ether, propylene glycol,polyoxyethylene hardened castor oil, a heterocyclic thioester or ketone,and perfume. The resulting mixture is stirred, and purified water isadded to the mixture to obtain a liquid.

The liquid may be applied once to 4 times per day to a site havingmarked baldness or alopecia.

Example 10

A shampoo comprising the following composition may be prepared. (%)Sodium laurylsulfate 5.0 Triethanolamine laurylsulfate 5.0 Betainelauryldimethylaminoacetate 6.0 Ethylene glycol distearate 2.0Polyethylene glycol 5.0 a heterocyclic thioester or ketone as defined5.0 above Ethanol 2.0 Perfume 0.3 Purified water 69.7

Into 69.7 of purified water are added 5.0 g of sodium laurylsulfate, 5.0g of triethanolamine laurylsulfate, 6.0 g of betainelauryldimethyl-aminoacetate. Then a mixture obtained by adding 5.0 g ofa heterocyclic thioester or ketone, 5.0 of polyethylene glycol, and 2.0g of ethylene glycol distearate to 2.0 g of ethanol, followed by string,and 0.3 g of perfume are successively added. The resulting mixture isheated and subsequently cooled to obtain a shampoo.

The shampoo may be used on the scalp once or twice per day.

Example 11

A patient is suffering from alopecia senilis. A heterocyclic thioesteror ketone as identified above, or a pharmaceutical compositioncomprising the same, may be administered to the patient. Increased hairgrowth is expected to occur following treatment.

Example 12

A patient is suffering from male pattern alopecia. A heterocyclicthioester or ketone as identified above, or a pharmaceutical compositioncomprising the same, may be administered to the patient. Increased hairgrowth is expected to occur following treatment.

Example 13

A patient is suffering from alopecia areata. A heterocyclic thioester orketone as identified above, or a pharmaceutical composition comprisingthe same may be administered to the patient. Increased hair growth isexpected to occur following treatment.

Example 14

A patient is suffering from hair loss caused by skin lesions. Aheterocyclic thioester or ketone as identified above, or apharmaceutical composition comprising the same, may be administered tothe patient. Increased hair growth is expected to occur followingtreatment.

Example 15

A patient is suffering from hair loss caused by tumors. A heterocyclicthioester or ketone as identified above, or a pharmaceutical compositioncomprising the same, may be administered to the patient. Increased hairgrowth is expected to occur following treatment.

Example 16

A patient is suffering from hair loss caused by a systematic disorder,such as a nutritional disorder or an internal secretion disorder. Aheterocyclic thioester or ketone as identified above, or apharmaceutical composition comprising the same, may be administered tothe patient. Increased hair growth is expected to occur followingtreatment.

Example 17

A patient is suffering from hair loss caused by chemotherapy. Aheterocyclic thioester or ketone as identified above, or apharmaceutical composition comprising the same, may be administered tothe patient. Increased hair growth is expected to occur followingtreatment.

Example 18

A patient is suffering from hair loss caused by radiation. Aheterocyclic thioester or ketone as identified above, or apharmaceutical composition comprising the same, may be administered tothe patient. Increased hair growth is expected to occur followingtreatment.

The invention being thus described, it will be obvious that the same maybe varied in many ways. Such variations are not to be regarded as adeparture from the spirit and scope of the invention and all suchmodifications are intended to be included within the scope of thefollowing claims.

1. A method for treating alopecia or promoting hair growth in an animal,which comprises administering to said animal an effective amount of aheterocyclic thioester or ketone.
 2. The method of claim 1, wherein theheterocyclic thioester or ketone is non-immunosuppressive.
 3. The methodof claim 1, wherein the heterocyclic thioester or ketone has an affinityfor an FKBP-type immunophilin.
 4. The method of claim 3, wherein theFKBP-type immunophilin is FKBP-12. 5-36. (Canceled)
 37. A pharmaceuticalcomposition which comprises: (i) an effective amount of a heterocyclicthioester or ketone for treating alopecia or promoting hair growth in ananimal; and (ii) a pharmaceutically acceptable carrier.
 38. Thepharmaceutical composition of claim 37, wherein the heterocyclicthioester or ketone is non-immunosuppressive.
 39. The pharmaceuticalcomposition of claim 37, wherein the heterocyclic thioester or ketonehas an affinity for an FKBP-type immunophilin.
 40. The pharmaceuticalcomposition of claim 39, wherein the FKBP-type immunophilin is FKBP-12.41. The pharmaceutical composition of claim 37, wherein the heterocyclicthioester or ketone is a compound of formula I

or a pharmaceutically acceptable salt, ester, or solvate thereof,wherein: A and B, taken together with the nitrogen and carbon atoms towhich they are respectively attached, form a 5-7 membered saturated orunsaturated heterocyclic ring containing, in addition to the nitrogenatom, one or more additional O, S, SO, SO₂, N, NH, or NR₂ heteroatom(s);X is either O or S; Z is either S, CH₂, CHR₁ or CR₁R₃; W and Y areindependently O, S, CH₂ or H₂; R₁ and R₃ are independently C₁-C₆straight or branched chain alkyl or C₂-C₆ straight or branched chainalkenyl, wherein said alkyl or alkenyl is substituted with one or moresubstituent(s) independently selected from the group consisting of(Ar₁)_(n), C₁-C₆ straight or branched chain alkyl or C₂-C₆ straight orbranched chain alkenyl substituted with (Ar₁)_(n), C₃-C₈ cycloalkyl,C₁-C₆ straight or branched chain alkyl or C₂-C₆ straight or branchedchain alkenyl substituted with C₃-C₈ cycloalkyl, and Ar₂; n is 1 or 2;R₂ is either C₁-C₉ straight or branched chain alkyl, C₂-C₉ straight orbranched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl or Ar_(n),wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is eitherunsubstituted or substituted with one or more substituent(s)independently selected from the group consisting of C₁-C₄ straight orbranched chain alkyl, C₂-C₄ straight or branched chain alkenyl, andhydroxy; and Ar₁ and Ar₂ are independently an alicyclic or aromatic,mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein said ringis either unsubstituted or substituted with one or more substituent(s)independently selected from the group consisting of halo, hydroxy,nitro, trifluoromethyl, C₁-C₆ straight or branched chain alkyl, C₂-C₆straight or branched chain alkenyl, C₁-C₄ alkoxy, C₂-C₄ alkenyloxy,phenoxy, benzyloxy, and amino; wherein the individual ring size is 5-8members; and wherein the heterocyclic ring has 1-6 heteroatom(s)independently selected from the group consisting of O, N, and S.
 42. Thepharmaceutical composition of claim 41, wherein the mono- or bicyclic,carbo- or heterocyclic ring is selected from the group consisting ofnaphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl, quinolinyl,isoquinolinyl, fluorenyl, and phenyl.
 43. The pharmaceutical compositionof claim 37, wherein the heterocyclic thioester or ketone is a compoundof formula II

or a pharmaceutically acceptable salt, ester, or solvate thereof,wherein: n is 1 or 2; X is O or S; Z is selected from the groupconsisting of S, CH₂, CHR₁, and CR₁R₃; R₁ and R₃ are independentlyselected from the group consisting of C₁-C₅ straight or branched chainalkyl, C₂-C₅ straight or branched chain alkenyl, and Ar₁, wherein saidalkyl, alkenyl or AR₁ is unsubstituted or substituted with one or moresubstituent(s) independently selected from the group consisting of halo,nitro, C₁-C₆ straight or branched chain alkyl, C₂-C₆ straight orbranched chain alkenyl, hydroxy, C₁-C₄ alkoxy, C₂-C₄ alkenyloxy,phenoxy, benzyloxy, amino, and Ar₁; R₂ is selected from the groupconsisting of C₁-C₉ straight or branched chain alkyl, C₂-C₉ straight orbranched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, and Ar₁;and Ar₁ is phenyl, benzyl, pyridyl, fluorenyl, thioindolyl or naphthyl,wherein said Ar₁ is unsubstituted or substituted with one or moresubstituent(s) independently selected from the group consisting of halo,trifluoromethyl, hydroxy, nitro, C₁-C₆ straight or branched chain alkyl,C₂-C₆ straight or branched chain alkenyl, C₁-C₄ alkoxy, C₂-C₄alkenyloxy, phenoxy, benzyloxy, and amino.
 44. The pharmaceuticalcomposition of claim 43, wherein: n is 1; and x is O.
 45. Thepharmaceutical composition of claim 44, wherein Z is CH₂.
 46. Thepharmaceutical composition of claim 45, wherein the compound is selectedfrom the group consisting of: (2S)-2-({1-Oxo-5-phenyl}-pentyl-1-(3,3-dimethyl-1,2-dioxopentyl)pyrrolidine;3,3-Dimethyl-1-[(2S)-2-(5-(3-pyridyl)pentanoyl)-1-pyrrolidine]-1,2-pentanedione; (2S)-2-({1-Oxo-4-phenyl}-butyl-1-(3,3-dimethyl-1,2-dioxobutyl)pyrrolidine;(2S) -2-({1-Oxo-4-phenyl}-butyl-1-(2-cyclohexyl-1,2-dioxoethyl)pyrrolidine 2-({1-Oxo-4-phenyl}-butyl-1-(3,3-dimethyl-1,2-dioxobutyl)pyrrolidine; 1-{(2S)-2-[5,5-di(4-Fluorophenyl)pentanoyl]-2-pyrrolidine}-3,3-dimethyl-1,2-pentanedione;and pharmaceutically acceptable salts, esters, and solvates thereof. 47.The pharmaceutical composition of claim 44, wherein Z is S.
 48. Thepharmaceutical composition of claim 47, wherein the compound is selectedfrom the group consisting of: 2-Phenyl-1-ethyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;(3-Thioindolyl)methyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;2-Phenyl-1-ethyl(2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;2-Phenyl-1-ethyl(2S)-1-(1-cyclopencyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;3-Phenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;3-(3-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;3-Phenyl-1-propyl(2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;4-Phenyl-1-butyl(2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;4-Phenyl-1-butyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;3-(3-Pyridyl)-1-propyl(2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;3,3-Diphenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;3,3-Diphenyl-1-propyl(2S)-1-(2-Cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate;3-(para-Methoxyphenyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;3,3-Di(para-Fluoro)phenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate;4,4-Di(para-fluorophenyl)butyl1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;3-(1-Naphthyl)propyl(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;2,2-Diphenylethyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)tetrahydro-1H-2-pyrrolidinecarbothioate;3-[4-(Trifluoromethyl)phenyl]propyl(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;3-(2-Naphthyl)propyl(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;3-(3-Chlorophenyl)propyl(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;3-[3-(Trifluoromethyl)phenyl]propyl(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;3-(1-Biphenyl)propyl(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;3-(2-Fluorophenyl)propyl(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;3-(3-Fluorophenyl)propyl(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;3-(2-Chlorophenyl)propyl(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate;3-(3,4-Dimethoxyphenyl)propyl(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate; andpharmaceutically acceptable salts, esters, and solvates thereof.
 49. Thepharmaceutical composition of claim 48, wherein the compound is3,3-Diphenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate or apharmaceutically acceptable salt, ester, or solvate thereof.
 50. Thepharmaceutical composition of claim 48, wherein the compound is3-(1-Naphthyl)propyl(2S)-1-3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate or apharmaceutically acceptable salt, ester, or solvate thereof.
 51. Thepharmaceutical composition of claim 48, wherein the compound is2,2-Diphenylethyl (2S)-1-(3, 3-dimethyl-2-oxopencanoyl)tetrahydro-1H-2-pyrrolidinecarbothioate or a pharmaceutically acceptablesalt, ester, or solvate thereof.
 52. The pharmaceutical composition ofclaim 48, wherein the compound is 3-[4-(Trifluoromethyl)phenyl]propyl(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate or apharmaceutically acceptable salt, ester, or solvate thereof.
 53. Thepharmaceutical composition of claim 48, wherein the compound is3-(2-Naphthyl)propyl (2S)-i-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate or apharmaceutically acceptable salt, ester, or solvate thereof.
 54. Thepharmaceutical composition of claim 43, wherein: n is 1, and x is S. 55.The pharmaceutical composition of claim 54, wherein Z is CH₂.
 56. Thepharmaceutical composition of claim 54, wherein Z is S.
 57. Thepharmaceutical composition of claim 43, wherein: n is 2; and X is O. 58.The pharmaceutical composition of claim 57, wherein Z is CH₂.
 59. Thepharmaceutical composition of claim 58, wherein the compound is selectedfrom the group consisting of:2-({1-Oxo-6-phenyl}-hexyl-1-(2-cyclohexyl-1,2-dioxoethyl ) piperidine;3,3-Dimethyl-1-[2-(4-phenylpentanoyl)piperidino]-1,2-pentanedione; andpharmaceutically acceptable salts, esters, and solvates thereof.
 60. Thepharmaceutical composition of claim 57, wherein Z is S.
 61. Thepharmaceutical composition of claim 60, wherein the compound is selectedfrom the group consisting of: 2-Phenyl-1-ethyl1-(3,3-dimethyl-1,2-dioxopentyl)-2-piperidinecarbothioate;2-Phenyl-1-ethyl 1-(2-phenyl-1,2-dioxoethyl)-2-piperidinecarbothioate;3-Phenyl-1-propyl1-(3,3-dimethyl-1,2-dioxobutyl)-2-piperidinecarbothioate;4-Phenyl-1-butyl1-(1,2-dioxo-3,3-dimethylbutyl)-2-piperidinecarbothioate;1,5-Diphenyl-3-pentyl1-(3,3-dimethyl-1,2-dioxopentyl)-2-piperidinecarbothioate;1,5-Diphenyl-3-mercaptopentyl1-(3-phenyl-1,2-dioxoethyl)-2-piperidinecarbothioate;3-(para-Methoxyphenyl)-1-propyl 1-(1,2-dioxo-3,3-dimethylpentyl)piperidine-2-carbothioate; 3-(para-Methoxyphenyl)-1-propyl1-(2-phenyl-1,2-dioxoethyl) piperidine-2-carbothioate;3-(1-Naphthyl)-1-propyl 1-(3,3-dimethyl-1,2-dioxopentyl)piperidine-2-carbothioate; 2,2-Diphenylethyl(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;3,3-Diphenylpropyl1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;3-(2-Naphthyl)propyl(2R,S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;4-Phenylbutyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;3-Phenylpropyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;3-(2-Chlorophenyl)propyl1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate;3-(2-Fluorophenyl)propyl1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate; and3-(3-Fluorophenyl)propyl1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate; andpharmaceutically acceptable salts, esters, and solvates thereof.
 62. Thepharmaceutical composition of claim 61, wherein the compound is3,3-Diphenylpropyl1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate or apharmaceutically acceptable salt, ester, or solvate thereof.
 63. Thepharmaceutical composition of claim 43, wherein: n is 2; and X is S. 64.The pharmaceutical composition of claim 63, wherein Z is CH₂.
 65. Thepharmaceutical composition of claim 63, wherein Z is S.
 66. Thepharmaceutical composition of claim 63, wherein Z is CHR₁.
 67. Thepharmaceutical composition of claim 66, wherein the compound is2-({1-Oxo-[2-{2′-phenyl}ethyl]-4-phenyl}-butyl-1-(3,3-dimethyl-1,2-dioxobutyl)piperidine.68. The pharmaceutical composition of claim 37, wherein the heterocyclicthioester or ketone is a compound formula III

or a pharmaceutically acceptable salt, ester, or solvate thereof,wherein: A, B, and C are independently CH₂, O, S, SO, SO₂, NH or NR₂; Xis O or S; Z is S, CH₂, CHR₁, or CR₁R₃; R₁ and R₃ are independentlyC₁-C₆ straight or branched chain alkyl or C₂-C₆ straight or branchedchain alkenyl, wherein said alkyl or alkenyl is substituted with one ormore substituent(s) independently selected from the group consisting of(Ar₁)_(n), C₁-C₆ straight or branched chain alkyl or C₂-C₆ straight orbranched chain alkenyl substituted with (Ar₁)_(n), C₃-C₈ cycloalkyl,C₁-C₆ straight or branched chain alkyl or C₂-C₆ straight or branchedchain alkenyl substituted with C₃-C₈ cycloalkyl, and Ar₂; R₂ is eitherC₁-C₉ straight or branched chain alkyl or C₂-C₉ straight or branchedchain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl or Ar₁, wherein saidalkyl, alkenyl, cycloalkyl or cycloalkenyl is either unsubstituted orsubstituted with one or more substituent(s) independently selected fromthe group consisting of C₁-C₄ straight or branched chain alkyl, C₂-C₄straight or branched chain alkenyl, and hydroxy; and Ar₁ and Ar₂ areindependently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo-or heterocyclic ring, wherein said ring is either unsubstituted orsubstituted with one or more substituent(s) independently selected fromthe group consisting of halo, hydroxy, nitro, trifluoromethyl, C₁-C₆straight or branched chain alkyl, C₂-C₆ straight or branched chainalkenyl, C₁-C₄ alkoxy, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino;wherein the individual ring size is 5-8 members; and wherein theheterocyclic ring contains 1-6 heteroatom(s) independently selected fromthe group consisting of O, N, and S.
 69. The pharmaceutical compositionof claim 68, wherein: A is CH₂; B is CH₂ or S; C is CH₂ or NH; X is O orS; Z is S or CH₂; R₁ is 2-phenethyl or 3-phenylpropyl; and R₂ is1,1-dimethylpropyl.
 70. The pharmaceutical composition of claim 37,wherein the heterocyclic thioester or ketone is a compound is of formulaIV

or a pharmaceutically acceptable salt, ester, or solvate thereof,wherein: A, B, C and D are independently CH₂, O, S, SO, SO₂, NH, or NR₂;X is O or S; Z is S, CH₂, CHR₁, or CR₁R₃; R₁ and R₃ are independentlyC₁-C₆ straight or branched chain alkyl or C₂-C₆ straight or branchedchain alkenyl, wherein said alkyl or alkenyl is substituted with one ormore substituent(s) independently selected from the group consisting of(Ar₁)_(n), C₃-C₆ straight or branched chain alkyl or C₂-C₆ straight orbranched chain alkenyl substituted with (Ar₁)_(n), C₃-C₈ cycloalkyl,C₁-C₆ straight or branched chain alkyl or C₂-C₆ straight or branchedchain alkenyl substituted with C₃-C₈ cycloalkyl, and Ar₂; n is 1 or 2;R₂ is either C₁-C₉ straight or branched chain alkyl or C₂-C₉ straight orbranched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl or Ar₁,wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is eitherunsubstituted or substituted with one or more substituent(s)independently selected from the group consisting of C₁-C₄ straight orbranched chain alkyl, C₂-C₄ straight or branched chain alkenyl, andhydroxy; and Ar₁ and Ar₂ are independently an alicyclic or aromatic,mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein said ringis either unsubstituted or substituted with one or more substituent(s)independently selected from the group consisting of halo, hydroxy,nitro, trifluoromethyl, C₁-C₆ straight or branched chain alkyl, C₂-C₆straight or branched chain alkenyl, C₁-C₄ alkoxy, C₂-C₄ alkenyloxy,phenoxy, benzyloxy, and amino; wherein the individual ring size is 5-8members; and wherein the heterocyclic ring has 1-6 heteroatom(s)independently selected from the group consisting of O, N, and S.
 71. Thepharmaceutical composition of claim 70, wherein: A is CH₂; B is CH₂; Cis S or O; D is CH₂; X is O; Z is CH₂ or S; R₁ is 3-phenylpropyl or2-phenethyl; and R₂ is 1,1-dimethylpropyl.
 72. The pharmaceuticalcomposition of claim 37, wherein the heterocyclic thioester or ketone isa compound of formula V

or a pharmaceutically acceptable salt, ester, or solvate thereof,wherein: V is C, N or S; A and B, taken together with V and the carbonatom to which they are respectively attached, form a 5-7 memberedsaturated or unsaturated heterocyclic ring containing, in addition to V,one or more heteroatom(s) independently selected from the groupconsisting of O, S, SO, SO₂, N, NH, and NR₄; R₄ is either C₁-C₉ straightor branched chain alkyl, C₂-C₉ straight or branched chain alkenyl, C₃-C₉cycloalkyl, C₅-C₇ cycloalkenyl, or Ar₃, wherein R₄ is eitherunsubstituted or substituted with one or more substituent(s)independently selected from the group consisting of halo, haloalkyl,carbonyl, carboxy, hydroxy, nitro, trifluoromethyl, C₁-C₆ straight orbranched chain alkyl, C₂-C₆ straight or branched chain alkenyl, Cl-C₄alkoxy, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, thioalkyl, alkylthio,sulfhydryl, amino, alkylamino, aminoalkyl, aminocarboxyl, and Ar₄; Ar₃and Ar₄ are independently an alicyclic or aromatic, mono-, bi- ortricyclic, carbo- or heterocyclic ring; wherein the individual ring sizeis 5-8 members; wherein said heterocyclic ring contains 1-6heteroatom(s) independently selected from the group consisting of O, N,and S; and R₁, R₂, W, X, Y, and Z are as defined in claim 41 above.